Melanoma is a type of cancer primarily affecting the skin that develops from pigment-containing cells known as melanocytes. The primary cause of melanoma is ultraviolet light (UV) exposure in those with low levels of skin pigment, which causes damage to DNA in skin cells. The UV light may be from either the Sun or from tanning devices. About 25% of melanomas develop from moles. Individuals with many moles, a history of affected family members, or who have poor immune function are all at greater risk of developing a melanoma. A number of rare genetic defects also increase the risk of developing melanoma. Diagnosis of melanoma is typically done by visual inspection of any concerning lesion followed by biopsy.
Treatment of melanoma is typically removal by surgery. In those with slightly larger cancers nearby lymph nodes may be tested for spread. Most people are cured if spread has not occurred. In those in whom melanoma has spread, immunotherapy, biologic therapy, radiation therapy, or chemotherapy may improve survival. With treatment, the five-year survival rate in the United States is 98% among those with localized disease, but only 17% among those in whom spread has occurred. Melanoma is considered the most dangerous type of skin cancer. Globally, in 2012, it occurred in 232,000 people and resulted in 55,000 deaths.
Tumor mutations, including mutations associated with melanoma, create specific neoantigens that can be recognized by the immune system. Roughly 50% of melanomas are associated with an endogenous T-cell response. Cytotoxic T-cells (CT cells, or cytotoxic T lymphocytes (CTLs)) are leukocytes which destroy virus-infected cells and tumor cells, and are also implicated in transplant rejection. CTLs that express the CD8 glycoprotein at their surfaces are also known as CD8+ T-cells or CD8+ CTLs. Tumors develop a variety of mechanisms of immune evasion, including local immune suppression in the tumor microenvironment, induction of T-cell tolerance, and immunoediting. As a result, even when T-cells infiltrate the tumor they cannot kill the cancer cells. An example of this immunosuppression in cancer is mediated by a protein known as programmed cell death 1 (PD-1) which is expressed on the surface of activated T-cells. If another molecule, called programmed cell death 1 ligand 1 or programmed cell death 1 ligand 2 (PD-L1 or PD-L2), binds to PD-1, the T-cell becomes inactive. Production of PD-L1 and PD-L2 is one way that the body naturally regulates the immune system. Many cancer cells make PD-L1, hijacking this natural system and thereby allowing cancer cells to inhibit T-cells from attacking the tumor.
One approach to the treatment of cancer is to interfere with the inhibitory signals produced by cancer cells, such as PD-L1 and PD-L2, to effectively prevent the tumor cells from putting the brakes on the immune system. Recently, an anti-PD-1 monoclonal antibody, known as nivolumab, marketed as Opdivo®, was approved by the Food and Drug Administration for treatment of patients with unresectable or metastatic melanoma who no longer respond to other drugs. In addition, nivolumab was approved for the treatment of squamous and non-squamous non-small cell lung cancer and renal cell carcinoma. Nivolumab has also been approved in melanoma in combination with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibody. Nivolumab acts as an immunomodulator by blocking ligand activation of the PD-1 receptor on activated T-cells. In contrast to traditional chemotherapies and targeted anti-cancer therapies, which exert their effects by direct cytotoxic or tumor growth inhibition, nivolumab acts by blocking a negative regulator of T-cell activation and response, thus allowing the immune system to attack the tumor. PD-1 blockers appear to free up the immune system only around the tumor, rather than more generally, which could reduce side effects from these drugs.
The current clinical results of anti-PD-1 treatment in melanoma patients are encouraging and overall results lead to progression free and overall survival results that are superior to alternative therapies. However, the real promise of these therapies is related to durable responses and long-term clinical benefit seen in a subgroup of around 40% of melanoma patients. Some portion of the other ˜60% of patients might do better on alternative therapies. Being able to select which patients derive little benefit from anti-PD-1 treatment from pre-treatment samples would enable better clinical understanding and enhance the development of alternative treatments for these patients. There is also considerable cost related to these therapies, e.g. the recently approved combination of ipilimumab and nivolumab in melanoma while showing spectacular results is only effective in about 55% of patients while costing around $295,000 per treatment course. (Leonard Saltz, Md., at ASCO 2015 plenary session: “The Opdivo+Yervoy combo is priced at approximately 4000× the price of gold ($158/mg)”). This results in a co-pay of around $60,000 for patients on a standard Medicare plan. Avoiding this cost by selecting these treatments only for those patients who are likely to benefit from them would result in substantial savings to the health care system and patients. It is also unclear whether the benefit of the combination of nivolumab and ipilimumab arises from a synergistic effect, or is just the sum of different patient populations responding to either nivolumab or ipilimumab. In any case having a test for nivolumab benefit would shed light on this question.
Much work has been performed to use the expression of PD-L1 measured by immunohistochemistry (IHC) as a biomarker for selection of anti-PD-1 treatments. Correlations between anti-PD-1 efficacy and outcome have been observed in some studies but not in others. Of particular issue is the current lack of standardization and universally accepted cut-offs in terms of IHC staining, which renders comparison of such data difficult. Of more fundamental issue is the observation that PD-L1 expression appears to be a dynamic marker, i.e. IHC expression changes during tumor evolution and during treatment. If one were to use PD-L1 expression via IHC in a rigorous manner one would require multiple repeat biopsies with a high corresponding risk and cost for patients. In contrast, a serum based test would not suffer from these effects.
The assignee Biodesix, Inc. has developed classifiers for predicting patient benefit or non-benefit of certain anticancer drugs using mass spectrometry of blood-based samples. Representative patents include U.S. Pat. Nos. 7,736,905, 8,914,238; 8,718,996; 7,858,389; 7,858,390; and U.S. patent application publications 2013/0344111 and 2011/0208433.